Motivation for Cocaine and Non-Drug Reinforcers: Targeting Glutamate Homeostasis

Cocaine is the most commonly used illicit stimulant in the United States. Despite great strides in our understanding of the neuropharmacological underpinnings of cocaine addiction in the preclinical arena, the number of cocaine users in the United States has remained relatively stable in recent years, indicating that more clinical research is necessary to translate these findings to humans in an attempt to develop more effective means of reducing cocaine use. Emerging data suggest that perturbations in glutamate transmission following cocaine use (i.e., disrupted glutamate homeostasis) contribute to the maladaptive pattern of drug taking characterized by cocaine addiction. Specifically, preclinical studies indicate that cocaine exposure results in increased motivation to take cocaine and decreased drive for non-drug reinforcers. This change in reinforcer salience corresponds with complex neuropharmacological changes in the glutamate system. Whereas preclinical data suggest that targeting glutamate systems, specifically restoring glutamate homeostasis, reduces drug reinforcer salience, this research area remains relatively unexplored in humans. Some initial studies suggest that n-acetylcysteine pretreatment normalizes glutamate levels in cocaine users and that n-acetylcysteine maintenance attenuates desire for cocaine and attention to cocaine cues in abstinent cocaine-dependent subjects. Whether restoration of glutamate homeostasis impacts motivation for drug relative to non-drug reinforcers remains to be determined in humans. The research proposed here will demonstrate that restoration of glutamate homeostasis reduces motivation to take cocaine and increases motivation to obtain a non-drug alternative reinforcer (i.e., money) in cocaine-dependent humans using progressive-ratio schedules of reinforcer availability, which are an accepted means to measure motivation. The use of concurrent progressive-ratio schedules of drug and non-drug reinforcer availability will allow inferences to be made about the influence of restored glutamate homeostasis on motivation to obtain these two types of reinforcers. Cognitive tasks that assess domains relating to reinforcer choice also will be included to complement the self-administration outcomes. This study will translate findings from preclinical research and provide the initial clinical evidence that restoration of glutamate homeostasis shifts reinforcer salience away from drug reinforcers towards non-drug reinforcers in active cocaine users. Outcomes of the experiment will not only contribute to our understanding of the clinical neuropharmacology of cocaine addiction, they also can be used to guide development of treatments for cocaine use disorders.